Emetine, a potent alkaloid for the treatment of SARS-CoV-2 targeting papain-like protease and non-structural proteins: pharmacokinetics, molecular docking and dynamic studies.

The main objective of this study is to find out the anti-SARS-CoV-2 potential of emetine by using molecular docking and dynamic simulation approaches. Interestingly, molecular docking studies suggest that Emetine showed significant binding affinity toward Nsp15 (-10.8 kcal/mol) followed by Nsp12 (-9.5 kcal/mol), RNA-dependent RNA polymerase, RdRp (-9.5 kcal/mol), Nsp16 (-9.4 kcal/mol), Nsp10 (-9.2 kcal/mol), Papain-like protein (-9.0 kcal/mol), Nsp13 (-9.0 kcal/mol), Nsp14 (-8.9 kcal/mol) and Spike Protein Receptor Domain (-8.8 kcal/mol) and chymotrypsin-like protease, 3CLpro (-8.5 kcal/mol), respectively, which are essential for viral infection and replication. In addition, molecular dynamic simulation (MD) was also performed for 140 ns to explore the stability behavior of the main targets and inhibitor complexes as well as the binding mechanics of the ligand to the target proteins. The obtained MD results followed by absolute binding energy calculation confirm that the binding of emetine at the level of the various receptors is more stable. The complex EmetineNSP15, mechanistically was stabilized as follows: Emetine first binds to the monomer, after, binds to the second inducing the formation of a dimer which in turn leading to the formation of complex that simulation stabilizes it at a value less than 5 Å. Overall, supported by the powerful and good pharmacokinetic data of Emetine, our findings with clinical trials may be helpful to confirm that Emetine could be promoted in the prevention and eradication of COVID-19 by reducing the severity in the infected persons and therefore can open possible new strategies for drug repositioning. Communicated by Ramaswamy H. Sarma.

Tripeptides from Allium subhirsitum L. extracts: Pharmacokinetics properties, toxicity prediction and in silico study against SARS-CoV-2 enzymes and pro-inflammatory proteins.

Developing new prophylactic and therapeutic agents with broad-spectrum antiviral activities is urgently needed to combat emerging human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since no available clinically antiviral drugs have been approved to eradicate COVID-19 as of the writing of this report, this study aimed to investigate bioactive short peptides from Allium subhirsutum L. (Hairy garlic) extracts identified through HR-LC/MS analysis that could potentially hinder the multiplication cycle of SARS-CoV-2 via molecular docking study. The obtained promising results showed that the peptides (Asn-Asn-Asn) possess the highest binding affinities of -8.4 kcal/mol against S protein, (His-Phe-Gln) of -9.8 kcal/mol and (Gln-His-Phe) of -9.7 kcal/mol towards hACE2, (Thr-Leu-Trp) of -10.3 kcal/mol and (Gln-Phe-Tyr) of -9.8 kcal/mol against furin. Additionally, the identified peptides show strong interactions with the targeted and pro-inflammatory ranging from -8.1 to -10.5 kcal/mol for NF-κB-inducing kinase (NIK), from -8.2 to -10 kcal/mol for phospholipase A2 (PLA2), from -8.0 to -10.7 kcal/mol for interleukin-1 receptor-associated kinase 4 (IRAK-4), and from -8.6 to -11.6 kcal/mol for the cyclooxygenase 2 (COX2) with Gln-Phe-Tyr model seems to be the most prominent. Results from pharmacophore, drug-likeness and ADMET prediction analyses clearly evidenced the usability of the peptides to be developed as an effective drug, beneficial for COVID-19 treatment.

Antiviral Effects of Artemisinin and Its Derivatives against SARS-CoV-2 Main Protease: Computational Evidences and Interactions with ACE2 Allelic Variants.

Fighting against the emergent coronavirus disease (COVID-19) remains a big challenge at the front of the world communities. Recent research has outlined the potential of various medicinal herbs to counteract the infection. This study aimed to evaluate the interaction of artemisinin, a sesquiterpene lactone extracted from the Artemisia genus, and its derivatives with the SARS-CoV-2 main protease. To assess their potential use against COVID-19, the interactions of the main active principle of Artemisia with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) was investigated through in silico probing. Our results showed that artemesinin and its derivatives manifested good oral absorption and bioavailability scores (0.55). They potently bound to the Mpro site of action-specifically, to its Cys145 residue. The selected compounds established two to three conventional hydrogen bonds with binding affinities ranging between -5.2 and -8.1 kcal/mol. Furthermore, artemisinin interactions with angiotensin converting enzyme 2 (ACE2) were dependent on the ACE2 allelic variants. The best score was recorded with rs961360700. A molecular dynamic simulation showed sufficient stability of the artemisinin-Mpro complex on the trajectory of 100 ns simulation frame. These binding interactions, together with drug-likeness and pharmacokinetic findings, confirmed that artemisinin might inhibit Mpro activity and explain the ethnopharmacological use of the herb and its possible antiviral activity against SARS-CoV-2 infection inducing COVID-19. Nevertheless, it interacted differently with the various ACE2 allelic variants reported to bind with the SARS-CoV-2 spike protein.

Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro.

Considering the urgency of the COVID-19 pandemic, we developed a receptor-based pharmacophore model for identifying FDA-approved drugs and hits from natural products. The COVID-19 main protease (Mpro) was selected for the development of the pharmacophore model. The model consisted of a hydrogen bond acceptor, donor, and hydrophobic features. These features demonstrated good corroboration with a previously reported model that was used to validate the present model, showing an RMSD value of 0.32. The virtual screening was carried out using the ZINC database. A set of 208,000 hits was extracted and filtered using the ligand pharmacophore mapping, applying the lead-like properties. Lipinski's filter and the fit value filter were used to minimize hits to the top 2000. Simultaneous docking was carried out for 200 hits for natural drugs belonging to the FDA-approved drug database. The top 28 hits from these experiments, with promising predicted pharmacodynamic and pharmacokinetic properties, are reported here. To optimize these hits as Mpro inhibitors and potential treatment options for COVID-19, bench work investigations are needed.

Computational hunting of natural active compounds as an alternative for Remdesivir to target RNA-dependent polymerase.

The hunt for potential lead/drug molecules from different resources, especially from natural resources, for possible treatment of COVID-19 is ongoing. Several compounds have already been identified, but only a few are good enough to show potential against the virus. Among the identified druggable target proteins of SARS-CoV-2, this study focuses on non-structural RNA-dependent RNA polymerase protein (RdRp), a well-known enzyme for both viral genome replication and viral mRNA synthesis, and is therefore considered to be the primary target. In this study, the virtual screening followed by an in-depth docking study of the Compounds Library found that natural compound Cyclocurcumin and Silybin B have strong interaction with RdRp and much better than the remdesivir with free binding energy and inhibition constant value as êzŒ-6.29 kcal/mol and 58.39 µMêzŒ, and êzŒ-7.93kcal/mol and 45.3 µMêzŒ, respectively. The finding indicated that the selected hits (Cyclocurcumin and Silybin B) could act as non-nucleotide anti-polymerase agents, and can be further optimized as a potential inhibitor of RdRp by benchwork experiments.

Chloroquine and Hydroxychloroquine Interact Differently with ACE2 Domains Reported to Bind with the Coronavirus Spike Protein: Mediation by ACE2 Polymorphism.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection inducing coronavirus disease 2019 (COVID-19) is still an ongoing challenge. To date, more than 95.4 million have been infected and more than two million deaths have been officially reported by the WHO. Angiotensin-converting enzyme (ACE) plays a key role in the disease pathogenesis. In this computational study, seventeen coding variants were found to be important for ACE2 binding with the coronavirus spike protein. The frequencies of these allele variants range from 3.88 × 10-3 to 5.47 × 10-6 for rs4646116 (K26R) and rs1238146879 (P426A), respectively. Chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are mainly used to prevent and treat malaria and rheumatic diseases. They are also used in several countries to treat SARS-CoV-2 infection inducing COVID-19. Both CQ and HCQ were found to interact differently with the various ACE2 domains reported to bind with coronavirus spike protein. A molecular docking approach revealed that intermolecular interactions of both CQ and HCQ exhibited mediation by ACE2 polymorphism. Further explorations of the relationship and the interactions between ACE2 polymorphism and CQ/HCQ would certainly help to better understand the COVID-19 management strategies, particularly their use in the absence of specific vaccines or drugs.

Plants-Derived Biomolecules as Potent Antiviral Phytomedicines: New Insights on Ethnobotanical Evidences against Coronaviruses.

SARS-CoV-2 infection (COVID-19) is in focus over all known human diseases, because it is destroying the world economy and social life, with increased mortality rate each day. To date, there is no specific medicine or vaccine available against this pandemic disease. However, the presence of medicinal plants and their bioactive molecules with antiviral properties might also be a successful strategy in order to develop therapeutic agents against SARS-CoV-2 infection. Thus, this review will summarize the available literature and other information/data sources related to antiviral medicinal plants, with possible ethnobotanical evidence in correlation with coronaviruses. The identification of novel antiviral compounds is of critical significance, and medicinal plant based natural compounds are a good source for such discoveries. In depth search and analysis revealed several medicinal plants with excellent efficacy against SARS-CoV-1 and MERS-CoV, which are well-known to act on ACE-2 receptor, 3CLpro and other viral protein targets. In this review, we have consolidated the data of several medicinal plants and their natural bioactive metabolites, which have promising antiviral activities against coronaviruses with detailed modes of action/mechanism. It is concluded that this review will be useful for researchers worldwide and highly recommended for the development of naturally safe and effective therapeutic drugs/agents against SARS-CoV-2 infection, which might be used in therapeutic protocols alone or in combination with chemically synthetized drugs.

Identification of Persuasive Antiviral Natural Compounds for COVID-19 by Targeting Endoribonuclease NSP15: A Structural-Bioinformatics Approach.

SARS-CoV-2 is a positive-stranded RNA virus that bundles its genomic material as messenger-sense RNA in infectious virions and replicates these genomes through RNA intermediates. Several virus-encoded nonstructural proteins play a key role during the viral life cycle. Endoribonuclease NSP15 is vital for the replication and life cycle of the virus, and is thus considered a compelling druggable target. Here, we performed a combination of multiscoring virtual screening and molecular docking of a library of 1624 natural compounds (Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products (NuBBE) database) on the active sites of NSP15 (PDB:6VWW). After sequential high-throughput screening by LibDock and GOLD, docking optimization by CDOCKER, and final scoring by calculating binding energies, top-ranked compounds NuBBE-1970 and NuBBE-242 were further investigated via an indepth molecular-docking and molecular-dynamics simulation of 60 ns, which revealed that the binding of these two compounds with active site residues of NSP15 was sufficiently strong and stable. The findings strongly suggest that further optimization and clinical investigations of these potent compounds may lead to effective SARS-CoV-2 treatment.

Current status and strategic possibilities on potential use of combinational drug therapy against COVID-19 caused by SARS-CoV-2.

The spread of new coronavirus infection starting December 2019 as novel SARS-CoV-2, identified as the causing agent of COVID-19, has affected all over the world and been declared as pandemic. Approximately, more than 8,807,398 confirmed cases of COVID-19 infection and 464,483 deaths have been reported globally till the end of 21 June 2020. Until now, there is no specific drug therapy or vaccine available for the treatment of COVID-19. However, some potential antimalarial drugs like hydroxychloroquine and azithromycin, antifilarial drug ivermectin and antiviral drugs have been tested by many research groups worldwide for their possible effect against the COVID-19. Hydroxychloroquine and ivermectin have been identified to act by creating the acidic condition in cells and inhibiting the importin (IMPα/ß1) mediated viral import. There is a possibility that some other antimalarial drugs/antibiotics in combination with immunomodulators may help in combatting this pandemic disease. Therefore, this review focuses on the current use of various drugs as single agents (hydroxychloroquine, ivermectin, azithromycin, favipiravir, remdesivir, umifenovir, teicoplanin, nitazoxanide, doxycycline, and dexamethasone) or in combinations with immunomodulators additionally. Furthermore, possible mode of action, efficacy and current stage of clinical trials of various drug combinations against COVID-19 disease has also been discussed in detail.Communicated by Ramaswamy H. Sarma.